Acute renal failure occurs late in the course and is a major cause of death in patients with acute edematous lung injury (ARDS). The mechanism by which the kidney is damaged in ARDS is unknown Recent evidence suggests that activated neutrophils and endotoxin, which are present in the blood of patients with ARDS, are important mediators of cell injury. The present hypothesis is that compared to the lung, the kidney is relatively resistant to injury by complement, endotoxin and/or neutrophils unless a preceding or superimposed ischemia/reperfusion insult has also occurred. Ischemia/reperfusion worsens injury by endotoxin and.or neutrophils by causing release of xanthine oxidase derived oxygen metabolites by he kidney which can directly injure kidney cells and predispose kidney cells to activated neutrophils by depleting cells of endogenous oxygen metabolite scavengers, enhancing neutrophil recruitment and inactivating circulation antiproteases. The preliminary data support this hypothesis. Blood levels of complement. endotoxin and neutrophils are increased in patients with ASRDS. In isolated perfused kidneys, neutrophils do not cause renal injury unless first activated by stimulators such as phorbol myristate acetate. Severe ischemia/reperfusion insults to kidneys cause neutrophils recruitment and neutrophils worsen ischemia.reperfusion injury in kidneys undergoing reperfusion after severe ischemic insults. The immediate specific objectives are to determine: 1) the effect of endotoxin, activated complement components and/or neutrophils alone and/or in combination on the structure and functions of the isolated perfused kidney; and 2) the effect of mild ischemia/reperfusion insults on the development of renal in injury in kidneys perfused with endoxotin, activated complement components and/or neutrophils. The significance of these studies is to improve understanding of mechanisms of kidney injury in ARDS. This new information may also be relevant to understanding the mechanisms by which ischemia/reperfusion predisposes to many other nephrotoxins, including antibiotics, anti-tumor drugs, hemoglobin and myoglobin.